New Candidate Vaccines against Blood-StagePlasmodium falciparumMalaria: Prime-Boost Immunization Regimens Incorporating Human and Simian Adenoviral Vectors and Poxviral Vectors Expressing an Optimized Antigen Based on Merozoite Surface Protein 1

Abstract

Although merozoite surface protein 1 (MSP-1) is a leading candidate vaccine antigen for blood-stage malaria, its efficacy in clinical trials has been limited in part by antigenic polymorphism and potentially by the inability of protein-in-adjuvant vaccines to induce strong cellular immunity. Here we report the design of novel vectored Plasmodium falciparum vaccines capable of overcoming such limitations. We optimized an antigenic insert comprising the four conserved blocks of MSP-1 fused to tandemly arranged sequences that represent both allelic forms of the dimorphic 42-kDa C-terminal region. Inserts were expressed by adenoviral and poxviral vectors and employed in heterologous prime-boost regimens. Simian adenoviral vectors were used in an effort to circumvent preexisting immunity to human adenoviruses. In preclinical studies these vaccines induced potent cellular immune responses and high-titer antibodies directed against MSP-1. The antibodies induced were found to have growth-inhibitory activity against dimorphic allelic families of P. falciparum. These vectored vaccines should allow assessment in humans of the safety and efficacy of inducing strong cellular as well as cross-strain humoral immunity to P. falciparum MSP-1.

Enhancing Blood-Stage Malaria Subunit Vaccine Immunogenicity in Rhesus Macaques by Combining Adenovirus, Poxvirus, and Protein-in-Adjuvant Vaccines

“…Generation of viral vector and protein vaccines rAdCh63 and markerless rMVA vectors expressing P. falciparum AMA1 were generated and purified using methods that were described previously (11,31). The vectors express a 3483-bp biallelic AMA1 transgene composed of the human tPA leader sequence (9), followed by aa 25-546 of the ectodomain of AMA1 (strain 3D7) (GenBank Accession #U65407; http://www.…”

“…These vectored vaccines can induce qualitatively different types of immune responses to protein-in-adjuvant vaccines, including high-titer Th1 isotypeskewed Ab responses and, most notably, strong T cell responses (9). Abs induced by such regimens in mice and rabbits against MSP1 and AMA1 were shown to inhibit the growth of P. falciparum in vitro (10,11), and vaccination with an adenovirus-MVA regimen can protect mice against a lethal challenge with bloodstage P. yoelii (9). Importantly, CD8 + T cells against MSP1 can also reduce the P. yoelii liver-stage parasite burden, given that this Ag is expressed by parasites toward the end of hepatic development (12), and another study documented the ability of CD4 + T cells against AMA1 to contribute to blood-stage immunity against P. chabaudi rodent malaria, independently of Ab (13).…”

“…In recent years, viral-vectored blood-stage malaria vaccines have also been developed (7,8). Heterologous primeboost immunization regimens, involving replication-defective adenoviruses of human or simian serotype or the orthopoxvirusmodified vaccinia virus Ankara (MVA), have shown particular promise in mice and rabbits (9)(10)(11). These vectored vaccines can induce qualitatively different types of immune responses to protein-in-adjuvant vaccines, including high-titer Th1 isotypeskewed Ab responses and, most notably, strong T cell responses (9).…”

Assessment of Immune Interference, Antagonism, and Diversion following Human Immunization with Biallelic Blood-Stage Malaria Viral-Vectored Vaccines and Controlled Malaria Infection

“…The composition of the biallelic vaccine inserts for MSP1 (34,35) and AMA1 (32, 33) used in both the ChAd63 and MVA vaccine vectors have been previously described. In the case of AMA1, a bivalent transgene was optimized to consist of the 3D7 and FVO strain alleles fused in tandem, whereas for MSP1 an insert was designed comprising both the 3D7/ MAD20 and Wellcome alleles of the dimorphic 42-kDa C-terminal region (MSP1 42 /sequence blocks 16 and 17) fused in tandem and preceded by the naturally conserved regions of MSP1 sequence (blocks 1, 3, 5, and 12) (35).…”

“…Attempts to address this issue of antigenic polymorphism have involved the development of multivalent vaccine formulations containing multiple allelic variants of the MSP1 or AMA1 target Ag (28)(29)(30) or artificial diversity covering consensus sequences (31). Similarly, both of the viral-vectored vaccine transgene inserts had been previously designed to address the issues surrounding target Ag polymorphism by encoding biallelic vaccine inserts for AMA1 (32,33) and MSP1 (34,35). Although these strategies aim to confront the difficulties surrounding the induction of cross-strain humoral immunity, other reports have raised important concerns about this approach in the context of T cell immunity (36).…”